Emesis is the act of vomiting and can be described as the forceful expulsion of gastrointestinal contents through the mouth brought about by the descent of the diaphragm and powerful contractions of the abdominal muscles. Emesis is usually, but not always, preceded by nausea (the unpleasant feeling that one is about to vomit). Retching or dry heaves involves the same physiological mechanisms as vomiting, but occurs against a closed glottis, which prohibits the expulsion of gastric contents. Vomiting, nausea, retching or combinations thereof can be caused by a number of factors including, but not limited to, anesthetics, radiation, cancer chemotherapeutic agents, toxic agents, odors, medicines, for example, serotonin reuptake inhibitors, analgesics such as morphine, antibiotics and antiparasitic agents, pregnancy and motion. Conditions which are associated with vertigo (e.g., Meniere's disease and vestibular neuronitis) can also cause nausea, vomiting, retching or any combination thereof. Headache, caused by, for example, migraine, increased intracranial pressure or cerebral vascular hemorrhage can also result in nausea, vomiting, retching or any combination thereof. In addition, certain maladies of the gastrointestinal (GI) tract, for example, cholecystitis, choledocholithiasis, intestinal obstruction, acute gastroenteritis, perforated viscus, dyspepsia resulting from, for example, gastroesophageal reflux disease, peptic ulcer disease, gastroparesis, gastric or esophageal neoplasms, infiltrative gastric disorders (e.g., Menetrier's syndrome, Crohn's disease, eosinophilic gastroenteritis, sarcoidosis and amyloidosis),gastric infections (e.g., CMV, fingal, TB and syphilis), parasites (e.g., Giardia lamblia and Strongyloides stercoralis), chronic gastric volvulus, chronic intestinal ischemia, altered gastric motility disorders and/or food intolerance or Zollinger-Ellison syndrome can result in vomiting, nausea, retching or any combination thereof. However, in some cases of vomiting, nausea, retching or any combination thereof, no etiology can be determined despite extensive diagnostic testing (e.g., Cyclic Vomiting Syndrome).
Nausea, vomiting and retching are defined as acute when symptoms are present for less than a week. The causes of nausea, vomiting and retching of short duration are often separable from etiologies leading to more chronic symptoms.
Nausea, vomiting and retching are defined as chronic when symptoms are present for over a week. For example, symptoms can be continuous or intermittent and last for months or years.
The vomiting reflex is triggered by stimulation of chemoreceptors in the upper GI tract and mechanoreceptors in the wall of the GI tract which are activated by both contraction and distension of the gut as well as by physical damage. A coordinating center in the central nervous system controls the emetic response. This center is located in the parvicellular reticular formation in the lateral medullary region of the brain. Afferent nerves to the vomiting center arise from abdominal splanchnic and vagal nerves, vestibulo-labyrinthine receptors, the cerebral cortex and the chemoreceptor trigger zone (CTZ). The CTZ lies adjacent in the area postrema and contains chemoreceptors that sample both blood and cerebrospinal fluid. Direct links exist between the emetic center and the CTZ. The CTZ is exposed to emetic stimuli of endogenous origin (e.g., hormones) as well as to stimuli of exogenous origin, such as drugs. The efferent branches of cranial nerves V, VII and IX, as well as the vagus nerve and sympathetic trunk produce the complex coordinated set of muscular contractions, cardiovascular responses and reverse peristalsis that characterize vomiting.
Of significant clinical relevance is the nausea and vomiting resulting from the administration of general anesthetics (commonly referred to as, post-operative nausea and vomiting, PONV), chemotherapeutic agents and radiation therapy.
In fact, the symptoms caused by the chemotherapeutic agents can be so severe that the patient refuses further treatment. Three types of emesis are associated with the use of chemotherapeutic agents. The first, is acute emesis, which occurs within the first 24 hours of chemotherapy. The second, is delayed emesis which occurs 24 hours or more after chemotherapy administration. The third, is anticipatory emesis, which begins prior to the administration of chemotherapy, usually in patients whose emesis was poorly controlled during a previous chemotherapy cycle.
PONV is also an important patient problem and one that patients rate as the most distressing aspect of operative procedure, even above pain. Consequently, the need for an effective anti-emetic in this area is important. As a clinical problem PONV is troublesome and requires staff around to ensure that vomitus is not regurgitated, which can have very serious clinical sequelae. Further, there are certain operative procedures where it is clinically important that patients do not vomit. For example, in ocular surgery where intra-cranial ocular pressure can increase to the extent that stitches are ruptured and the operative procedure is set back in terms of success to a marked degree.
There are a number groups of agents that are used clinically for the treatment of emesis. These groups include: anticholinergics, antihistamines, phenothiazines, butyrophenones, cannabinoids, benzamides, glucocorticoids, benzodiazepines and 5-HT3 receptor antagonists. In addition, tricyclic antidepressants have also been used on a limited basis.
The phenothiazines, which include prochlorperazine and chlorpromazine, block dopamine type-2 receptors in the CTZ. However, the side effects, for example, extrapyramidal symptoms, such as, dystonia and akathisia, sedation, anticholinergic effect and orthostatic hypotension make the use of the phenothiazines a less than desirable therapy.
Anticholinergics used in the treatment of nausea and vomiting, include scopolomine (e.g., in treating motion sickness). However, drowsiness is a significant side effect.
Antihistamines (dimenhydrinate and diphenhydramine) are mainly used for motion sickness and in antiemetic combinations to reduce extrapyramidal side effects of dopamine receptor antagonists. As a single agent, the antihistamines have modest antiemetic activity and include sedation and anticholinergic effects as the major drawbacks.
Butyrophenones, for example, haloperidol and droperidol, work by blocking dopamine receptors in the CTZ. The side effects of butyrophenones include akathisia, dystonia and hypotension.
Cannabinoids such as tetrahydrocannabinol and nabilone have shown limited efficacy (see, e.g. Sallan et al., N. Eng. J. Med., 302: 135–138 (1980)). In addition, the side effects include euphoria, dizziness, paranoid ideation and somnolence.
Benzamides include, for example, metoclopramide, cisapride and trimethobenzamide. However, side effects which include extrapyramidal symptoms and diarrhea make the use of benzamides a less than desirable therapy.
Benzodiazapines include, for example, lorazepam. Side effects of the benzodiazapines include perceptual disturbances, urinary incontinence, hypotension, diarrhea, sedation and amnesia.
Corticosteroids such as dexamethasone and methylprednisolone are useful in combination therapy, but shown little efficacy as a single agent. Side effects include, hyperglycemia, euphoria, insomnia and rectal pain.
The antiemetic property of tricyclic antidepressants has been assessed on a limited basis (see, e.g., Prakash et al., Dig. Dis. Sci. 43(9):1951–1956 (1998)) and cyclic vomiting syndrome (Prakash and Clouse,Am. J. Gastroenterol., 94(10): 2855–2860 (1999).
However, the undesirable side effects associated with the use of tricyclic antidepressants are a significant drawback for this therapy. For example, the anticholinergic properties of the tricyclic antidepressants can cause dry mouth, constipation, blurred vision, urinary retention, weight gain, hypertension and cardiac side effects, such as palpitations and arrhythmia.
Antagonism of the 5-HT3 receptor has been the focus of antiemetic therapy. More specifically, 5-HT3 receptors are widely distributed in the mammalian central, peripheral and enteric nervous systems. The enteric nervous system resides within the walls of the gastrointestinal tract. 5-HT3 receptors have been found to play an important role in the control of vomiting in a variety of mammals including humans (Veyrat-Follet et al., Drugs 53(2):206–234 (1997)). The receptors are present in the part of the brain that is involved in controlling vomiting as well as in the gastrointestinal tract. Receptors at both locations have been shown to be involved in vomiting. It is thought that 5-HT released from the enterochromaffin cells of the gastrointestinal mucosa acts on 5-HT3 receptors to initiate the vomiting reflex. Chemotherapy and radiotherapy, two important clinical causes of vomiting, can cause release of 5-HT from the enterochromaffin cells. Chemotherapeutic agents also appear to act directly on the chemoreceptor trigger zone (CTZ) of the vomiting center in the brain that then feeds onto neurons containing 5-HT3 receptors to initiate vomiting. That is, activation of the chemoreceptor trigger zone (CTZ) triggers the release of neurotransmitters that activate the vomiting center. CTZ neurotransmitters that are thought to cause emesis include, but are not limited to, dopamine, serotonin, histamine and norepinephrine.
However, improved treatment regimens are still needed. For example, the use of 5-HT3 receptor antagonists such as ondansetron, granisetron and tropisetron has been shown to be less effective for delayed nausea and vomiting than for acute symptoms. In addition, efficacy of the 5-HT3 receptor antagonists appears to be less pronounced for moderate emetogenic chemotherapy regimens than for cisplatin-containing regimens. Further, control over nausea appears to be significantly less than control over vomiting. Further, the efficacy of the agents appears to diminish across repeated days and across repeated chemotherapy cycles (see, e.g., Morrow et al., Cancer 76(3): 343–357 (1995)).
As such, improved methods for the treatment of vomiting, nausea, retcning or any combination thereof are needed.